Lymphangioleiomyomatosis

NORD gratefully acknowledges the members of the Scientific Advisory Board of the LAM Foundation for assistance in the preparation of this report and Joel Moss, MD, PhD at the National Heart, Lung, and Blood Insitute, National Institutes of Health, for reviewing this report.

Synonyms of Lymphangioleiomyomatosis

LAM

Lymphangioleimyomatosis

Lymphangioleiomatosis

Pulmonary Lymphangiomyomatosis

Sporadic Lymphangioleiomyomatosis

General Discussion

Lymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly affects women of childbearing age. It occurs in women who have tuberous sclerosis, and also in women who do not have a heritable genetic disorder. LAM is characterized by the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidney and lymphatics. Common symptoms associated with LAM include coughing and/or difficulty breathing (dyspnea), especially following periods of exercise or exertion. Affected individuals may also experience complications including collapse of a lung or fluid accumulation around the lungs (pleural effusion). The disorder is progressive and, in some cases, may result in chronic respiratory failure.

Signs & Symptoms

The symptoms of LAM vary from case to case. Specific symptoms depend upon which organs are affected by the LAM cells. In most cases, the initial symptoms involve the lung and include shortness of breath, especially upon exercise or exertion. Affected individuals may also experience episodes of chest pain, coughing, wheezing, and coughing up small amounts of blood (hemoptysis).

Some individuals may experience fluid (e.g. chyle) accumulation in the chest cavity around the lungs (pleural effusion). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with LAM, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax). In some cases, chyle may accumulate in the abdomen causing an increase in girth, a condition called chylous ascites. Involvement of the axial lympatics may also lead to formation fo lymphangioleiomyomas, chyle- filled lymphatic structures within the chest and abdomen.

Some individuals with LAM may experience collapse of a lung that is unrelated to trauma (spontaneous pneumothorax). The symptoms of a collapsed lung may include sudden, sharp chest pain; difficult, rapid breathing; rapid heartbeat (tachycardia); low blood pressure (hypotension); profuse sweating (diaphoresis); dizziness; and/or lack of normal chest movement on the affected side of the chest. A collapsed lung may recur in some individuals.

Approximately 50 percent of individuals with LAM develop angiomyolipomas, which are benign tumors made up of fat, blood vessels and smooth muscle like cells. These tumors affect the kidneys or abdomen and often do not cause symptoms (asymptomatic). In some cases, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen (abdominal hemorrhaging).

Symptoms of LAM may become progressively worse as LAM cell proliferation continues, eventually resulting in chronic life-threatening respiratory failure. The symptoms of LAM often worsen during pregnancy. Many cases of LAM are associated with osteoporosis, a condition characterized by progressive thinning of the bones.

Causes

The exact cause of LAM is not known. Since the disease occurs almost exclusively in females of reproductive age, it is possible that an association exists between female hormones (i.e., estrogen and progesterone) and LAM.

Some researchers are studying the connection between a rare genetic disorder known as tuberous sclerosis complex (TSC) and LAM. Approximately 30 percent of women with TSC show evidence of pulmonary lymphangioleiomyomatosis, suggesting that these disorders may share a common cause or origin. TSC is caused by mutations in one of two genes known as the TSC1 gene or TSC2 gene.

Recently, studies have shown that some individuals with LAM who do not have TSC have somatic mutations (e.g., mutations that occur in peripheral tissues after conception) in the TSC2 gene. These mutations were not found in the blood or the normal lung or normal kidney cells of affected individuals. These data suggest that TSC mutations are a cause of LAM even in women who do not have the heritable disorder, TSC.

The symptoms associated with LAM occur due to the spread and accumulation (proliferation) of LAM cells into various organs of the body, especially the lungs. This abnormal proliferation results in the formation of cysts as well as the obstruction of affected airways (breathing tubes), blood vessels, and lymph vessels. Infiltration of the lung with LAM cells may result in progressive breathing difficulties, lung collapse, and interference with the lung’s ability to deliver oxygen to the rest of the body.

Obstruction of blood vessels may result in bleeding in the lungs (pulmonary hemorrhage) and coughing up of blood (hemoptysis). Obstruction of lymph vessels may result in chylous effusions and ascites. Lymph vessels are part of the lymphatic system, a circulatory network of vessels, ducts, and nodes that filter and distribute lymph and blood cells throughout the body. Lymph is a fluid that circulates through the body cleaning and strengthening tissue. After performing its functions, lymph is drained away through the lymphatic system.

Affected Populations

LAM is a rare disorder that predominantly affects women of childbearing age. The average age of affected individuals at symptom onset is 33. More than 400 cases have been reported in the United States in the medical literature since Dr. Von Stossel first described the disorder in 1937. Some estimates suggest that more than 1,000 women in the United States may have LAM. Many researchers believe that the disorder in under-diagnosed, making it difficult to determine its true frequency in the general population. The Tuberous Sclerosis Association recommends that women with tuberous sclerosis should be screened for LAM at least once on reaching maturity.

Related Disorders

Symptoms of the following disorders can be similar to those of LAM. Comparisons may be useful for a differential diagnosis:

There are several obstructive lung diseases that can cause symptoms that are similar to LAM. However, these diseases, such as emphysema, asthma, and chronic obstructive bronchitis, can be ruled out with laboratory tests and radiographic (x-ray) studies.

Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth but may present in adulthood. The disorder may be characterized by episodes of uncontrolled electrical activity in the brain (seizures); mental retardation; distinctive skin abnormalities (lesions); and benign (noncancerous), tumor-like nodules (hamartomas) of the brain, certain regions of the eyes (e.g., retinas), the heart, the kidneys, the lungs, or other tissues or organs. In addition, many affected individuals may have cyst-like areas within certain skeletal regions, particularly bones of the fingers and toes (phalanges). Characteristic skin lesions include sharply defined areas of decreased skin coloration (hypopigmentation) that may develop during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, blend together (coalesce), and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including flat, “coffee-colored” areas of increased skin pigmentation (café-au-lait spots); benign, fibrous nodules (fibromas) arising around or beneath the nails; or rough, elevated, “knobby” lesions (shagreen patches) on the lower back. Approximately 30 percent of individuals with tuberous sclerosis develop pulmonary lymphangioleiomyomatosis. Tuberous sclerosis results from changes (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic) gene mutations, with no family history of the disease. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)

Langerhans cell histiocytosis (LCH) is a rare spectrum of disorders characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). The appearance of LCH in the lungs may have similarities to LAM on CT scans. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.)

Diagnosis

The diagnosis of LAM may be confirmed by a thorough clinical evaluation that includes a detailed patient history and a variety of specialized tests including radiographic (x-ray) studies, lung function tests, and/or surgical removal and microscopic study of affected tissue (biopsy). In about 80 percent of people with LAM, CT studies reveal cysts in the lungs in or around one or both lungs (pleural effusion). CT studies of the abdomen may reveal angiomyolipomas or lymphangioleiomyomas that support a diagnosis of LAM.

Surgical open lung biopsy is one definitive way to confirm the diagnosis of LAM. These biopsy tissue samples verify the presence of LAM cells.

Standard Therapies

Treatment

The treatment of LAM is directed toward the specific symptoms that are apparent in each individual. Fluid accumulation in the lungs (pleural effusion) may be drained by means of a surgically implanted shunt or tube. The surgical insertion of a sterile irritant (such as the antibiotic oxycycline) into the space surrounding the lungs can help to fuse the lung to the chest wall and reduce fluid accumulation around the lungs. Drugs that temporarily widen the bronchial tubes (bronchodilators) may help to alleviate breathing difficulties (asthma-like symptoms) in some cases. Supplemental oxygen should be administered as needed.

Rapamune (sirolimus) has been approved to treat lymphangioleiomyomatosis (LAM), a rare progressive lung disease that primarily affects women of childbearing age. Rapamune is manufactured by Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.

Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Some affected individuals have experienced symptomatic improvement while on this medication, especially those with recurrent chylous lung effusions, but routine use is not recommended because of significiant side effects. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

A fat replacement diet may or may not be beneficial for some women with chylothorax associated with LAM. Surgical removal of abdominal angiomyolipomas may be necessary in cases where these growths cause bleeding and pain. The initial recommendation is for the angiomyolipoma to be embolized, a procedure that may lead to necrosis of the lesion.

In individuals with severe cases of LAM, lung transplantation may be considered as a last resort. Other treatment is symptomatic and supportive.

Because of the frequent association of LAM with osteoporosis, affected individuals should have their bone mineral density tested. Any loss of bone mineral density should be treated with vitamin D and calcium supplementation and bisphosphonates.

Investigational Therapies

Scientists are investigating the role of hormone therapy in the development and onset of LAM. Some researchers have suggested that hormonal response markers (i.e., estrogen and progesterone receptor status) should be measured in lung tissue biopsy samples. It is hoped that, at some point, these studies may help to determine the best course of treatment. Hereditary factors are also being studied to help determine whether or not a genetic predisposition is essential to the development of LAM.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

Resources

RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.

Years Published

The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.

NORD's Rare Disease Database provides brief introductions for patients and their families to more than 1,200 rare diseases. This is not a comprehensive database since there are nearly 7,000 diseases considered rare in the U.S. We add new topics as we are able to do so, with the help of rare disease medical experts.

If you are seeking information about a rare disease that is not in this database, we would suggest contacting the Genetic and Rare Diseases Information Center (GARD) at the National Institutes of Health. NIH has the most complete database of rare diseases in the U.S.

Representatives of patient organizations whose medical advisors are interested in assisting NORD in creating a report on a disease not currently covered in this database may write to orphan@rarediseases.org.